The present invention concerns oligonucleotides, including antisense oligonucleotides, that are useful in the treatment of cancer, along with DNA encoding the same, vectors that contain such DNA, cells that express such DNA, pharmaceutical formulations containing the same, and methods of use thereof in the treatment of cancer.
Antisense oligonucleotides (along with other oligonucleotides that downregulate gene expression) offer the possibility of targeting a specific gene to study its function, inhibit its product, or repair a defect (A. Gewirtz et al., Facilitating oligonucleotide delivery: helping antisense deliver on its promise. Proc. Natl. Acad. Sci. USA, 93: 3161-3163, 1996; L. Long et al., Loss of the metastatic phenotype in murine carcinoma cells expressing an antisense RNA to the insulin-like growth factor receptor. Cancer Res., 55: 1006-1009, 1995; H. Sierakowska et al., Repair of thalassemic human xcex2-globin mRNA in mammalian cells by antisense oligonucleotides. Proc. Natl. Acad. Sci. USA, 93: 12840-12844, 1996). Antisense is therefore an appealing therapeutic strategy for malignancies, as it avoids some of the widely cytotoxic effects of current cancer therapy (J. Cheng et al., Amplification of AKT2 in human pancreatic cancer cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc. Natl. Acad. Sci. USA, 93: 3636-3641, 1996). Clinically, antisense offers an advantage over antibody-based targeting (T. Kishimoto et al., Phenotypes correlating to metastatic properties of pancreas adenocarcinoma in vivo: the importance of sialyl Lewis a antigen. Int. J. Cancer, 69: 290-294, 1996) because the constructs are often less immunogenic and have more favorable pharmacokinetics (J. Phillips et al., Pharmacokinetics, metabolism, and elimination of a 20-mer phosphorothioate oligodeoxynucleotide (CGP 69846A) after intravenous and subcutaneous administration. Biochem. Pharmacol., 54: 657-668, 1997). Accordingly, there is a continued need for new oligonucleotides that have anticancer activity.
A first aspect of the present invention is an oligonucleotide that hybridizes to a nucleic acid that encodes a fucosyltransferase (FUT). The fucosyltransferase is preferably FUT3 or FUT6.
A second aspect of the present invention is a pharmaceutical formulation comprising an oligonucleotide as described above in a pharmaceutically acceptable carrier. The oligonucleotide is included in an amount effective to treat a cancer as described herein, typically from about 0.01 percent to about 99 percent by weight of the formulation.
A third aspect of the present invention is a method of treating a subject afflicted with cancer (e.g., a carcinoma), comprising administering to the subject an oligonucleotide as described above in an amount effective to treat said cancer.
A fourth aspect of the present invention is a nucleic acid encoding an oligonucleotide that hybridizes to a nucleic acid that encodes a fucosyltransferase. The fucosyltransferase is preferably FUT3 or FUT6.
A fifth aspect of the present invention is a vector that contains and expresses a nucleic acid as described above.
A sixth aspect of the present invention is a pharmaceutical formulation comprising a vector as described above in a pharmaceutically acceptable carrier. The vector is included in an amount effective to treat cancer, typically from about 0.01 percent to about 99 percent by weight of the formulation.
A seventh aspect of the present invention is a method of treating a subject afflicted with cancer (e.g., a carcinoma), comprising administering to said subject a vector as described above in an amount effective to treat said cancer.
An eighth aspect of the present invention is a cell that contains and expresses a nucleic acid as described above.
The foregoing and other objects and aspects of the present invention are described in the figures herein and the specification set forth below.